Approximately 22 millions Americans suffer from chronic kidney disease (CKD), and 300,000 require renal replacement therapy for end stage kidney disease (ESRD). CKD patients are at significantly greater risk of having both fatal and non-fatal cardiovascular complications Renal replacement therapy prolongs the life of patients with ESRD, however, cardiovascular morbidity and mortality remains extremely high in the dialysis population. The propensity patients with kidney disease develop cardiac disease has been linked to a number of factors including heightened sympathetic tone, increased oxidative stress, and widespread arterial calcification. To investigate the pathogenesis of cardiac disease in CKD/ESRD, we hypothesized that the kidney's endocrine function was incompletely understood, that the organ secretes proteins that regulate cardiac function, and that these proteins could be identified using a combination of molecular methods and genetic database analysis. That effort led to the discovery of renalase, a novel FAD-dependent amine oxidase that is expressed in kidney, and heart. It is secreted into blood, and degrades circulating catecholamines. Renalase administration lowers blood pressure, and also protects against acute myocardial ischemia. Blood levels correlate positively with renal function, and patients with CKD and ESRD have low renalase levels. The molecular details of the renalase pathway are beginning to emerge, and we find that catecholamines regulate renalase gene expression, secretion and enzymatic activation. We hypothesize that renalase plays a key role in regulating catechlolamines levels and sympathetic activity, and that renalase deficiency in kidney disease results in heightened sympathetic tone, hypertension and increased cardiovascular risk. In the context of these findings and of the overall hypothesis, we propose to examine how catecholamines and/or blood pressure regulate blood renalase activity in vivo. We will study the mechanisms that mediate hypertension in the renalase knockout mouse. We will use transgenic animals to determine the specific contribution of the kidney to the renalase pathway. These studies will significantly enhance our understanding of the renalase pathway, and will begin to shed light on renalase's role in the pathogenesis of hypertension and cardiovascular complications associated with kidney disease. PUBLIC HEALTH RELEVANCE: Twenty millions Americans suffer from chronic kidney disease, and are at significantly greater risk for having both fatal and non-fatal cardiovascular complications. The pathogenesis of cardiac disease in this patient population is not well understood. Patients with kidney disease have a deficiency in renalase, a newly discovered hormone that is made in the kidney, is secreted in blood, and regulates blood pressure and cardiac function. Renalase itself or components of the renalase pathway may offer valuable therapeutic options for patients with kidney disease.